Introduction: Insight into susceptibility mechanisms underlying Parkinson's disease (PD) would aid the understanding of disease etiology, enable target finding and benefit the development of more refined disease-modifying strategies. Methods: We used intermittent low-dose MPTP (0.5 mg/kg/week) injections in marmosets and measured multiple behavioral and neurochemical parameters. Genetically diverse monkeys from different breeding families were selected to investigate inter- and intrafamily differences in susceptibility to MPTP treatment. Results: We show that such differences exist in clinical signs, in particular nonmotor PD-related behaviors, and that they are accompanied by differences in neurotransmitter levels. In line with the contribution of a genetic component, different susceptibility phenotypes could be traced back through genealogy to individuals of the different families. Conclusion: Our findings show that low-dose MPTP treatment in marmosets represents a clinically relevant PD model, with a window of opportunity to examine the onset of the disease, allowing the detection of individual variability in disease susceptibility, which may be of relevance for the diagnosis and treatment of PD in humans.

Keywords:
Parkinson, Marmoset, MPTP, Biochemistry, Behavior
1.
Dawson TM, Dawson VL: Molecular pathways of neurodegeneration in Parkinson's disease. Science 2003;302:819-822.
2.
Dexter DT, Jenner P: Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 2013;62:132-144.
3.
Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G: Missing pieces in the Parkinson's disease puzzle. Nat Med 2010;16:653-661.
4.
Reeve A, Simcox E, Turnbull D: Ageing and Parkinson's disease: why is advancing age the biggest risk factor? Age Res Rev 2014;14:19-30.
5.
Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, Schrag A: Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol 2012;72:893-901.
6.
Dauer W, Przedborski S: Parkinson's disease: mechanisms and models. Neuron 2003;39:889-909.
7.
Eslamboli A: Marmoset monkey models of Parkinson's disease: which model, when and why? Brain Res Bull 2005;68:140-149.
8.
Jenner P: From the MPTP-treated primate to the treatment of motor complications in Parkinson's disease. Parkinsonism Relat Disord 2009;15(suppl 4):S18-S23.
9.
Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983;219:979-980.
10.
Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D: Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 1999;46:598-605.
11.
Pifl C, Schingnitz G, Hornykiewicz O: Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on the regional distribution of brain monoamines in the rhesus monkey. Neuroscience 1991;44:591-605.
12.
Vezoli J, Dzahini K, Costes N, Wilson CRE, Fifel K, Cooper HM, Kennedy H, Procyk E: Increased DAT binding in the early stage of the dopaminergic lesion: a longitudinal [11C]PE2i binding study in the MPTP-monkey. Neuroimage 2014;102(part 2):249-261.
13.
Vezoli J, Fifel K, Leviel V, Dehay C, Kennedy H, Cooper HM, Gronfier C, Procyk E: Early presymptomatic and long-term changes of rest activity cycles and cognitive behavior in an MPTP-monkey model of Parkinson's disease. PLoS One 2011;6:e23952.
14.
Fifel K, Vezoli J, Dzahini K, Claustrat B, Leviel V, Kennedy H, Procyk E, Dkhissi-Benyahya O, Gronfier C, Cooper HM: Alteration of daily and circadian rhythms following dopamine depletion in MPTP treated non-human primates. PLoS One 2014;9:e86240.
15.
Korecka JA, Eggers R, Swaab DF, Bossers K, Verhaagen J: Modeling early Parkinson's disease pathology with chronic low dose MPTP treatment. Restor Neurol Neurosci 2013;31:155-167.
16.
Pain S, Gochard A, Bodard S, Gulhan Z, Prunier-Aesch C, Chalon S: Toxicity of MPTP on neurotransmission in three mouse models of Parkinson's disease. Exp Toxicol Pathol 2013;65:689-694.
17.
Verhave PS, Jongsma MJ, Van den Berg RM, Vis JC, Vanwersch RA, Smit AB, Van Someren EJ, Philippens IH: REM sleep behavior disorder in the marmoset MPTP model of early Parkinson disease. Sleep 2011;34:1119-1125.
18.
Verhave PS, Vanwersch RAP, van Helden HPM, Smit AB, Philippens IHCHM: Two new test methods to quantify motor deficits in a marmoset model for Parkinson's disease. Behav Brain Res 2009;200:214-219.
19.
van Vliet SAM, Vanwersch RAP, Jongsma MJ, van der Gugten J, Olivier B, Philippens IHCHM: Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects. Behav Pharmacol 2006;17:453-462.
20.
Philippens IH, Melchers BP, Roeling TA, Bruijnzeel PL: Behavioral test systems in marmoset monkeys. Behav Res Methods Instrum Comput 2000;32:173-179.
21.
Wolthuis OL, Groen B, Philippens IH: A simple automated test to measure exploratory and motor activity of marmosets. Pharmacol Biochem Behav 1994;47:879-881.
22.
Philippens IH, Wubben JA, Finsen B, 't Hart BA: Oral treatment with the NADPH oxidase antagonist apocynin mitigates clinical and pathological features of parkinsonism in the MPTP marmoset model. J Neuroimmune Pharmacol 2013;8:715-726.
23.
Davenport MD, Tiefenbacher S, Lutz CK, Novak MA, Meyer JS: Analysis of endogenous cortisol concentrations in the hair of rhesus macaques. Gen Comp Endocrinol 2006;147:255-261.
24.
Vegh MJ, de Waard MC, van der Pluijm I, Ridwan Y, Sassen MJ, van Nierop P, van der Schors RC, Li KW, Hoeijmakers JH, Smit AB, van Kesteren RE: Synaptic proteome changes in a DNA repair deficient ercc1 mouse model of accelerated aging. J Proteome Res 2012;11:1855-1867.
25.
Field A: Discovering Statistics Using IBM SPSS Statistics. London, Sage, 2013.
26.
Song L, Langfelder P, Horvath S: Random generalized linear model: a highly accurate and interpretable ensemble predictor. BMC Bioinformatics 2013;14:5.
27.
Winkler AM, Ridgway GR, Webster MA, Smith SM, Nichols TE: Permutation inference for the general linear model. Neuroimage 2014;92:381-397.
28.
Laird NM, Ware JH: Random-effects models for longitudinal data. Biometrics 1982;38:963-974.
29.
Lindstrom MJ, Bates DM: Newton-Raphson and EM algorithms for linear mixed-effects models for repeated-measures data. J Am Stat Assoc 1988;83:1014-1022.
30.
Pinheiro J, Bates D: Unconstrained parametrizations for variance-covariance matrices. Stat Comput 1996;6:289-296.
31.
Franke SK, van Kesteren RE, Wubben JA, Hofman S, Paliukhovich I, van der Schors RC, van Nierop P, Smit AB, Philippens IH: Progression and recovery of parkinsonism in a chronic progressive MPTP-induction model in the marmoset without persistent molecular and cellular damage. Neuroscience 2016;312:247-259.
32.
Schulz-Schaeffer WJ: Is cell death primary or secondary in the pathophysiology of idiopathic Parkinson's disease? Biomolecules 2015;5:1467-1479.
33.
Schulz-Schaeffer WJ: The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia. Acta Neuropathol 2010;120:131-143.
34.
Rommelfanger KS, Weinshenker D, Miller GW: Reduced MPTP toxicity in noradrenaline transporter knockout mice. J Neurochem 2004;91:1116-1124.
35.
Kilbourn MR, Sherman P, Abbott LC: Reduced MPTP neurotoxicity in striatum of the mutant mouse tottering. Synapse 1998;30:205-210.
36.
Ferris MJ, España RA, Locke JL, Konstantopoulos JK, Rose JH, Chen R, Jones SR: Dopamine transporters govern diurnal variation in extracellular dopamine tone. Proc Natl Acad Sci USA 2014;111:E2751-E2759.
37.
Kaplan JR, Manuck SB, Fontenot MB, Mann JJ: Central nervous system monoamine correlates of social dominance in cynomolgus monkeys (Macaca fascicularis). Neuropsychopharmacology 2002;26:431-443.
38.
Yodyingyuad U, de la Riva C, Abbott DH, Herbert J, Keverne EB: Relationship between dominance hierarchy, cerebrospinal fluid levels of amine transmitter metabolites (5-hydroxyindole acetic acid and homovanillic acid) and plasma cortisol in monkeys. Neuroscience 1985;16:851-858.
39.
Miller-Butterworth CM, Kaplan JR, Shaffer J, Devlin B, Manuck SB, Ferrell RE: Sequence variation in the primate dopamine transporter gene and its relationship to social dominance. Mol Biol Evol 2008;25:18-28.
40.
Larson ET, Summers CH: Serotonin reverses dominant social status. Behav Brain Res 2001;121:95-102.
41.
Korzan WJ, Forster GL, Watt MJ, Summers CH: Dopaminergic activity modulation via aggression, status, and a visual social signal. Behav Neurosci 2006;120:93-102.
42.
Shively CA, Grant KA, Ehrenkaufer RL, Mach RH, Nader MA: Social stress, depression, and brain dopamine in female cynomolgus monkeys. Ann NY Acad Sci 1997;807:574-577.
43.
Yanowitch R, Coccaro EF: The neurochemistry of human aggression; in Robert Huber DLB, Patricia B (eds): Advances in Genetics. Burlington, Academic Press, 2011, vol 75, chapt 7, pp 151-169.
44.
Tamashiro KL, Nguyen MM, Sakai RR: Social stress: from rodents to primates. Front Neuroendocrinol 2005;26:27-40.
45.
Lester D: A neurotransmitter basis for Eysenck's theory of personality. Psychol Rep 1989;64:189-190.
46.
Whitworth SR, Loftus AM, Skinner TC, Gasson N, Barker RA, Bucks RS, Thomas MG: Personality affects aspects of health-related quality of life in Parkinson's disease via psychological coping strategies. J Parkinsons Dis 2013;3:45-53.
© 2016 S. Karger AG, Basel
2016
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.